The arylamine moiety is a structural component in a variety of synthetic and naturally occurring biologically active compounds. For instance, arylamines are useful in a variety of applications such as in the preparation of dyes, herbicides, insecticides, pharmaceuticals, plant growth agents and antiknock agents for gasoline engines.
To further illustrate, primary anilines find a variety of utilities. p-Aminodiphenylamine is an important intermediate in the synthesis of antioxidants and antiozonants for rubber. Phenylenediamines, particularly C.sub.5 -C.sub.10 alkyl-substituted derivatives thereof, are also useful in stabilizing rubbers. p-Aminophenols are useful as chemical intermediates. For example, p-hydroxyaniline is employed in the manufacture of analgesics and antipyretics. Other substituted phenylamines, such as chloroanilines, are useful in the manufacture of dyes, medicinals, and resins.
Notwithstanding recent progress in the development of methods for the transition metal-catalyzed formation of carbon-heteroatom bonds, construction of the carbon-nitrogen bond of arylamines and vinylamines remains a synthetic challenge in certain cases. See, inter alia: U.S. Pat. No. 5,576,460; Angew. Chem., Int. Ed. Engl. 1995, 34, 1348; J Am. Chem. Soc. 1996, 118, 7215; Tetrahedron Lett. 1996, 52, 7525; and references cited therein. In particular, a number of synthetic methods for the construction of such an aryl-nitrogen bond suffer from severe reaction conditions and/or are only applicable to activated substrates. Typical routes to aromatic amines include nucleophilic aromatic substitution of electron-poor aryl precursors. See, Hattori et al. (1994) Synthesis 1994:199; and Bunnett, J. F. (1978) Acc. Chem. Res 1978 11:413. Synthesis of arylamines via copper-mediated Ullmann-like condensation reactions has also been reported. See, for example, Paine (1987) J. Am. Chem. Soc. 109:1496. The copper-catalyzed preparation of aryl amines, such as anilines and substituted anilines, by amination of an aryl halide is also described in U.S. Pat. No. 4,096,185, which discloses the preparation of p-aminobenzotrifluoride by reaction of p-chlorobenzotrifluoride with ammonia in the presence of a copper halide catalyst.
Primary anilines are often prepared by nitration of an arene, followed by reduction of the resulting nitroarene compound. The success of this approach hinges on three basic issues: 1) the availability of the arene starting material; 2) the ability to prepare the desired nitro compound from the arene; and 3) the ability to reduce selectively the nitro group to the corresponding primary aniline. This approach to anilines has certain inherent limitations. In some instances, the arene starting material is unavailable or difficult to obtain. In other instances, the directing effects of groups on the arene are such that the desired nitro compound is a minor product, or is not produced at all, in the nitration reaction. For example, m-toluidine is important as an intermediate in dyes and agricultural chemicals; application to toluene of the nitration-reduction approach, however, yields a mixture of toluidines comprising only a small percentage of m-toluidine. Finally, conditions required for reduction of the nitro group to the corresponding primary amine may be incompatible with other functional groups contained in the intermediate nitro arene.